Outcomes for Myeloma in the Era of Lenalidomide Maintenance Are Not Different Among Ethnic Groups Following Autologous Transplant

Abstract Background: Multiple myeloma (MM) is the most common hematological malignancy among African Americans (AA). The introduction of postransplant maintenance has had a significant improvement in progression free and overall survival for myeloma patients as demonstrated in large phase III clinical trials. However, the impact of race on the outcome of patients receiving maintenance treatment remains unknown. Methodology: We conducted a retrospective analysis of 299 consecutive patients transplanted for MM from 2005 to 2013 at the Winship Cancer Institute of Emory University. Survival analyses were estimated by Kaplan-Meier methods and univariate and multivariate analysis were performed using a cox proportional hazard model. Results: Baseline characteristics such as stage (International Staging System, ISS), presence of lytic lesions or plasmocytomas, immunoglobulin subtype, and cytogenetic risk category at presentation, were comparable between AA and white patients. Among AA, 57.1% received triple therapy with an immune modulator and a proteasome inhibitor (IMID+PI, lenalidomide (R) or thalidomide (T) and bortezomib (V) and dexamethasone), 49% received doublets (RD, TD or VD) and 29% received other bortezomib based regimens. In white patients 50.3% were treated with IMID+PI, 37% with doublets, 13.6% with received other bortezomib based regimens. Both populations had comparable ORR and >VGPR at day 100 (AA: ORR:90.74% and >VGPR:74.07% vs White ORR:90.65% and >VGPR: 77.57%, p>0.1). Of the 299 patients, 128 patients underwent maintenance treatment with lenalidomide (AA: 61 and White:67 patients) while 171 did not receive lenalidmode as they transplanted prior approval of lenalidomide maintenance. Maintenance treatments improved progression free survival in both ethnic cohorts. AA patients receiving maintenance therapy have not yet reached their median PFS with a median follow up of 8 years (60%), while median PFS was 4.8 years among those who did not receive maintenance (p=0.4). Similarly, in white patients, the PFS improved from 2.8 years without maintenance to 5.4 years with maintenance (p=0.01). Furthermore race did not affect PFS in both maintenance treated cohorts. Within the cohort of patients that did not receive maintenance therapy, we observed a trend of improvement in overall survival in AA patients ( p=0.06), which could suggest difference in the risk of the disease. However, no differences in staging or cytogenetics were identified between both ethnic groups at diagnosis that could explain this difference. Factors associated with longer PFS in univariate and multivariate analysis included AA race and immunoglobulin subtype (IgG and kappa light chain MM). In AA multivariate analysis identified the presence of lytic lesions as a factors associated with shorter PFS. In white patients, factors such as plasma cell leukemia at diagnosis were associated with worst PFS. In conclusion, race did not impact the improvement in PFS associated with post-transplant maintenance therapy. To our knowledge this preliminary analysis provides the first assessment of the influence of race in MM outcomes post-transplant during the lenalidomide maintenance era Disclosures Lonial: Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

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Effect of Timing and Duration of Maintenance Lenalidomide in Myeloma Patients after Autologous Stem Cell Transplantations

Blood ◽

10.1182/blood.v124.21.194.194 ◽

2014 ◽

Vol 124 (21) ◽

pp. 194-194

Author(s):

Idrees Mian ◽

Denai Milton ◽

Uday R. Popat ◽

Nina Shah ◽

Yago Nieto ◽

...

Keyword(s):

Overall Survival ◽

Maintenance Therapy ◽

Research Funding ◽

Maintenance Treatment ◽

Progression Free Survival ◽

Disease Status ◽

Hazard Ratio ◽

P Value ◽

Free Survival ◽

Late Initiation

Abstract Introduction: Maintenance lenalidomide after autologous hematopoietic stem cell transplantation (auto HCT) has been shown to improve progression free (PFS) and overall survival (OS) in myeloma patients. In this analysis we sought to determine the impact of lenalidomide treatment on achievement of complete remission (CR), survival and the incidence of secondary primary malignancies (SPM). Methods: We retrospectively analyzed all (N=466) consecutive myeloma patients who underwent auto HCT and received maintenance lenalidomide between August 2006 and September 2013 at our institution. Patients received doses of maintenance lenalidomide ranging from 5 mg – 15 mg/day or every other day. We looked at whether lenalidomide improved disease status, specifically CR in patients who had not achieved this before maintenance initiation and the median time to achieve CR. We also analyzed the effects of early initiation (<4-months after auto HCT) of maintenance lenalidomide versus late initiation (≥ 4-months after auto HCT) with regards to PFS and OS using the Kaplan-Meier method. Lastly we assessed if continuation of maintenance therapy beyond 2 and 3-years after auto HCT improved PFS and OS and increased the incidence of SPM. Results: The median follow-up time for all patients was 26.6 months. 173 patients (37%) experienced improvements in their disease status. Of these, 86 patients (50% of those with noted improvements and 19% of total patients assessed) who were not in CR before maintenance achieved CR while on maintenance. The average time to achieve CR in these patients was 12.9 months. Comparing the patients who were started on early maintenance treatment with those who were started on late maintenance therapy, we did not find any difference with regards to PFS (Hazard Ratio [HR]=0.90; p-value=0.57) and OS (HR=0.90; p-value=0.74). However, patients who had been on lenalidomide for > 2 years experienced a significant benefit in OS compared with those on lenalidomide for ≤ 2 years (HR=0.36; p-value=0.0015), although no difference in PFS was observed between the two cohorts (HR=0.77; p-value=0.18). A similar trend in OS was seen for patients who had been on lenalidomide > 3 years compared with those on maintenance treatment ≤ 3 years, though not statistically significant (HR=0.47; p-value=0.10). Again, no difference in PFS was noted between the two groups. Lastly there were only 12 cases of SPM reported in all patients assessed with no statistically significant association to the duration of lenalidomide use. In all 12 cases, lenalidomide was suspended and the mortality among these patients was 50%. Conclusions: Maintenance lenalidomide improves response rates after auto HCT in some patients including the CR rate, however, the median time to achieve CR in these patients is approximately 13 months. The patients who received maintenance therapy for > 2years had a significantly lower risk of death with a trend of improved OS in patients who continued maintenance therapy beyond 3-years. We conclude that the maintenance therapy should be continued for at least 2 years and possibly longer after auto HCT. Table 1 Summary of Survival Outcomes Maintenance Treatment Initiation Measure Early (N=155) Late (N=184) p-value Progression-free survival Hazard ratio (95% CI)a 0.90 (0.63, 1.30) 0.57 Overall survival Hazard ratio (95% CI)a 0.90 (0.49, 1.66) 0.74 Duration of Maintenance Treatment Measure > 2 years (N=115) ≤ 2 years (N=224) p-value Progression-free survival Hazard ratio (95% CI)b 0.77 (0.52, 1.13) 0.18 Overall survival Hazard ratio (95% CI)b 0.36 (0.19, 0.67) 0.0015 > 3 years (N=49) ≤ 3 years (N=290) p-value Progression-free survival Hazard ratio (95% CI)b 0.75 (0.45, 1.26) 0.28 Overall survival Hazard ratio (95% CI)b 0.47 (0.19, 1.15) 0.10 a Cox proportional hazards regression model: measure included as a baseline covariate with the following additional covariates: patient’s cytogenetic risk, creatinine, hemoglobin, B2-microglobulin, ISS stage at diagnosis, disease status at auto HCT, and response prior to auto HCT. b Cox proportional hazards regression model: measure included as a time-dependent covariate with the covariates listed above. Figure 1 Comparison of Overall Survival in Early vs Late initiation of Revlimid Figure 1. Comparison of Overall Survival in Early vs Late initiation of Revlimid Figure 2 Overall Survival – All Patients Figure 2. Overall Survival – All Patients Disclosures Shah: Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Array: Consultancy, Research Funding. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Bortezomib, Lenalidomide and Dexamethasone (VRD) Followed By Autologous Stem Cell Transplant for Newly Diagnosed Multiple Myeloma; The Mayo Clinic Experience

Blood ◽

10.1182/blood-2018-99-111147 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2147-2147

Author(s):

M Hasib Sidiqi ◽

Mohammed A Aljama ◽

Angela Dispenzieri ◽

Eli Muchtar ◽

Francis K. Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Maintenance Therapy ◽

Board Of Directors ◽

Mayo Clinic ◽

Research Funding ◽

Advisory Committees ◽

Post Transplant ◽

Standard Risk

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.

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Racial Disparity in Patients with Multiple Myeloma Are Blunted in the Era Novel Therapies

Blood ◽

10.1182/blood.v124.21.2525.2525 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2525-2525

Author(s):

Leon Bernal-Mizrachi ◽

Ajay K Nooka ◽

Chandra Pooja ◽

Monica S Chatwal ◽

Sungjin Kim ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Research Funding ◽

Response Rate ◽

Univariate Analysis ◽

Novel Agents ◽

Factors Associated ◽

Indolent Disease ◽

The Impact ◽

White Patients

Abstract Background: Multiple myeloma is the most common hematological malignancy among african americans (AA). Prior studies have shown conflicting results for outcomes based upon ethnicity following autologous stem cell transplantation (ASCT). However, much of this data is older, and predates the use of novel agents such as bortezomib (V), lenalidomide (R) and thalidomide (T). Methodology: We performed a retrospective analysis of 292 patients (147 AA and 145 Caucasian) treated with novel agents (proteasome inhibitors or immune modulators) and ASCT from 2006 to 2012 at the Winship Cancer Institute of Emory University to evaluate the impact of ethnicity on outcomes. Results: Baseline characteristics such as stage (International Staging System, ISS), presence of lytic lesions or plasmacytomas, immunoglobulin subtype, and cytogenetic risk category at presentation, were comparable between AA and white patients. Among AA, 112 (76.19%) patients received bortezomib containing regimens (VRD: 34.8%, VTD: 22.3%, VDTPACE:11%, VDD:10%, VD:19% and others bortezomib regimens 8%), 54 (36.7%) patients received lenalidomide (VRD: 34.8% or RD: 11.6%) and 72 (49%) patients received thalidomide (VTD: 22.3% or TD: 11.6%). In white patients 113 (77.93%) received bortezomib containing regimens (VRD: 33.1%, VTD: 17.2%, VDTPACE:9.6%, VDD: 1.4% and VD:11.7% and other bortezomib regimens 1.3%), 69 (47.6%) patients received lenalidomide containing regimens (VRD:33.1% and RD:11%) and 62 (42.8%) patients received thalidomide containing regimens (VTD: 17.2% or TD: 15%). A higher percentage of patients in the white cohort carried the antecedent diagnosis of monoclonal gammopathy in white patients (AA:0 vs white: 4.8%, p=0.007), and as expected, AA patients presented at a younger age when compared with whites (mean age of 55 vs 59 years, respectively, p<0.001). The overall response rate (ORR) of induction in the entire population was 86%, with an >VGPR of 58.8%. No difference was identified in pre-transplant ORR and >VGPR between AA (87.9% and 25.9%, respectively) and white patients (81.54% and 22.4%, respectively, p>0.1). Similarly, the ORR and >VGPR 100 days after transplantation was comparable between both ethnic groups (AA: OR:90.74% and >VGPR:74.07% vs white OR:90.65% and >VGPR: 77.57%, p>0.1). The depth of response after ASCT improved similarly in both groups (AA: 57.3% vs white: 67.7%, p=0.1). When the overall survival and progression free survival where evaluated, we found no significant differences between both cohorts. Factors associated with longer PFS in the population studied include AA race and the introduction of lenalidomide in the induction regimen. In AA patients univariate analysis identified early stage at presentation, indolent disease (prolong time from diagnosis to transplant), optimal pre-transplant response, and pre-transplant use of lenalidomide (HR:0.38 (0.18-0.8), p=0.01) as factors that potentially prolong PFS. Multivariate analysis identified the use of lenalidomide, as part of the pretransplant regimen, to reduce the risk of relapse (HR:0.38 (0.18-0.8), p=0.01) compared to bortezomib use (HR: 5.3 (2.11-11.98), p<0.001). In white patients, univariate and multivariate analysis identified that IgG and kappa light chain MM and indolent disease were factors associated with longer PFS, while history of plasma cell leukemia was related to shorter PFS. In conclusion, our results showed that novel agents have improved the response rate of both ethnic populations. From our preliminary analysis, it appears the PFS is longer among AA patients, suggesting a potential difference in MM biology of this patient population. Disclosures Lonial: Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

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A Randomized Phase III Trial of Thalidomide and Prednisone as Maintenance Therapy Following Autologous Stem Cell Transplantation (ASCT) In Patients with Multiple Myeloma (MM): The NCIC CTG MY.10 Trial

Blood ◽

10.1182/blood.v116.21.39.39 ◽

2010 ◽

Vol 116 (21) ◽

pp. 39-39 ◽

Cited By ~ 12

Author(s):

A. Keith Stewart ◽

Suzanne Trudel ◽

Nizar J Bahlis ◽

Darrell J White ◽

Waleed Sabry ◽

...

Keyword(s):

Quality Of Life ◽

Overall Survival ◽

Maintenance Therapy ◽

Research Funding ◽

Medical Condition ◽

Phase Iii ◽

Disease Stage ◽

Response Analysis ◽

Post Transplant

Abstract Abstract 39 Three randomized trials have previously reported a progression-free survival (PFS) advantage for patients receiving thalidomide (T) maintenance post ASCT in MM. Two trials reported an overall survival (OS) advantage but the largest trial reported shows no OS advantage and in very high risk MM the use of T was deleterious. Recent trial reports demonstrate a PFS but not yet an OS advantage for patients receiving maintenance lenalidomide. We report results of NCIC CTG MY.10 which compared treatment with T (200 mg daily) and prednisone (50 mg alternate days) (T/P) until progression versus observation alone when used as maintenance therapy following ASCT. Importantly, OS was the 1ry endpoint of this study, 2ry endpoints were PFS, quality of life (QoL), toxicity, and the incidence of venous thromboembolism events (VTE). Eligibility: Patients with MM who had ASCT within 1 year of beginning initial treatment for their disease. Patients were randomized 60–100 days post ASCT and had no other medical condition precluding long term use of T/P. Results: 332 patients were enrolled. Median age was 58 years and the arms were balanced. Patients were stratified by age (<60 or >60), and CR status post transplant. Median follow up is 4 years. Only 14% of patients were in CR post transplant. 111 patients died (50 versus 61 in T/P vs. observation). The median OS was 5 years for observation, and has not yet been reached for T/P, however T/P maintenance therapy did not significantly prolong OS: p = 0.18, HR of maintenance vs. observation 0.77 (95% CI 0.53–1.13). The 4 year survival rate was 68% for T/P and 60% for observation. Age and response to transplant had no significant association with OS (p=0.21), while higher disease stage was associated with shorter OS (p=0.03). The median PFS was 28 months for T/P versus 17 months for observation: p<0.0001, HR of T/P vs. observation 0.56 (95% CI 0.43 – 0.73). The 4 year PFS rate was 32% for T/P treated patients versus 14% for patients on observation. At relapse, treatment by arm (T/P vs observation) included lenalidomide (39 vs 34%), T (13 vs 22%) or bortezomib (50 versus 46%). Non hematologic toxicities were seen in more patients with treatment (Grade 3: 92% T/P vs 49% observation, grade 4: 16% vs 7%). Common toxicities of all grades that were significantly higher in T/P treated patients included hyperglycemia, edema, hypertension, fatigue, Cushingoid appearance, constipation, mouth dryness, dyspepsia, anxiety, memory loss, sensory neuropathy, tremor, blurred vision, depressed consciousness, cataracts, dyspnea and bruising. 7% of patients on maintenance T/P developed a VTE in the absence of prophylaxis versus 0% on observation. NCIC CTG standardized response analysis was use to compare QoL data between the 2 treatment arms. Overall, patients on T/P had worse QoL specifically in physical (p=0.07), role (p=0.08), cognitive (p = 0.01) and global (p=0.06) domains, and worse symptoms with dyspnea (p = 0.0007), constipation (p<0.0001), thirst (p=0.003), swelling in leg (p=0.03), numbness (p=0.02), dry mouth (p<0.0001), and balance problems (p<0.0001). However, patients on T/P reported improvement in appetite (p 0.02), and sleep (p=0.04). Conclusions: T/P maintenance did not improve overall survival, the primary objective of this trial, although a trend in favor of T/P was seen. In contrast, PFS was significantly improved in the T/P arm while toxicity was demonstrably increased and quality of life diminished. Disclosures: Stewart: Millennium: Consultancy; Celgene: Honoraria. Trudel:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Research Funding, Speakers Bureau. White:Celgene: Honoraria, Research Funding. Meyer:Celgene: Honoraria.

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Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1956-1956

Author(s):

Amy Wang ◽

Justin Kline ◽

Wendy Stock ◽

Satyajit Kosuri ◽

Andrew S. Artz ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Stem Cell ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Advisory Committees ◽

Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

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Open-Labeled, Multicenter Phase II Study of Bortezomib for Maintenance Therapy in Patients with High Risk Diffuse Large B Cell Lymphoma (DLBCL): Borma Trial from Consortium for Improving Survival of Lymphoma (CISL)

Blood ◽

10.1182/blood-2019-132192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2884-2884

Author(s):

Jae-Cheol Jo ◽

Ho Sup Lee ◽

Cheolwon Suh ◽

Hye Jin Kang ◽

Won Seog Kim ◽

...

Keyword(s):

High Risk ◽

Maintenance Therapy ◽

B Cell ◽

Research Funding ◽

Maintenance Treatment ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Risk Patients ◽

Large B Cell Lymphoma ◽

Risk Patients

Background: High-intermediate or high risk in international prognostic index (IPI) has a long-term chance of cure in the range about 50% in patients with diffuse large B cell lymphoma (DLBCL) treated by R-CHOP. These high risk patients should be considered for additional new treatment to standard R-CHOP or investigational approaches in the context of clinical trials that are designed to ensure that potentially curative therapy. Bortezomib inhibits NF-κB activation through proteasome inhibition, providing rationale for its use in cells that constitutively express NF-κB. Non-germinal center B cell (GCB) DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic NF-κB pathway, which can inhibit chemotherapy. There is no study of bortezomib as maintenance therapy after treated with R-CHOP in high risk patients with DLBCL. So we applied additional bortezomib as maintenance therapy in order to assess improving efficacy and survival rates in high risk patients with non-GCB DLBCL who had been confirmed complete response (CR) after treated with R-CHOP. Methods: Patients with newly diagnosed stage II(bulky)-IV DLBCL with high or high intermediate IPI score of 3 to 5, and patients achieving a CR at the end of 6 or 8 cycles of R-CHOP21 were eligible for enrollment. Non-GCB DLBCL according to Hans criteria confirmed by central review was need before enrollment. Bortezomib maintenance treatment was consisted of bortezomib 1.3mg/m2 subcutaneously administration day 1 and day 15 per 28-day cycle with a total of 12 cycles. The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoints were 3-year overall survival (OS), and toxicites. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Results: Fifty-nine patients were enrolled between May 2014 and Oct 2018. The type of Non-GCB DLBCL in all patients was confirmed by the central pathology review. The median age was 65 years (range: 27-86 years), and 60% were > 61 years. The baseline clinical features were as follows: female sex, 45.8%; ECOG >1, 10.2%; stage II bulky (>10cm), 6.8%; stage III/IV, 93.2%. At the time of analysis, 29 patients completed 12-cycles of bortezomib maintenance, and 3 patients is ongoing. Seven patients did not finished maintenance therapy due to toxicities (fatigue, atrial flutter, neuropathy, pleural effusion, thrombocytopenia), and withdrawal of informed consent (n=4). Sixteen patients experienced disease progression during bortezomib maintenance treatment. With a median follow-up of 25.1 months, 3-year PFS rate was 56.9% and 3-year OS rate was 86.4% (Figure 1). Toxicity was assessed in 489 cycles of bortezomib maintenance in all 59 patients. There was no treatment-related death and febrile neutropenia. Conclusion: Bortezomib maintenance showed 3-year PFS rate of 56.9% with acceptable toxicities in patients with high risk DLBCL achieving a CR at the end of 6 or 8 cycles of R-CHOP21. Figure 1 Disclosures Kim: Celltrion: Research Funding; Novartis: Research Funding; J + J: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

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Progression-Free Survival in Children With Optic Pathway Tumors: Dependence on Age and the Quality of the Response to Chemotherapy—Results of the First French Prospective Study for the French Society of Pediatric Oncology

Journal of Clinical Oncology ◽

10.1200/jco.2003.03.043 ◽

2003 ◽

Vol 21 (24) ◽

pp. 4572-4578 ◽

Cited By ~ 119

Author(s):

Véronique Laithier ◽

Jacques Grill ◽

Marie-Cécile Le Deley ◽

Marie-Madeleine Ruchoux ◽

Dominique Couanet ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Disease Progression ◽

Objective Response ◽

Progression Free Survival ◽

Optic Pathway ◽

Free Survival ◽

Factors Associated ◽

Response To Chemotherapy ◽

Risk Of Disease

Purpose: To evaluate a strategy aimed at avoiding radiotherapy during first-line treatment of children with progressive optic pathway tumors (OPT), by exclusively administering multiagent chemotherapy during 16 months. Patients and Methods: Between 1990 and 1998, 85 children with progressive OPT were enrolled onto this multicenter nationwide trial. Chemotherapy alternating procarbazine plus carboplatin, etoposide plus cisplatin, and vincristine plus cyclophosphamide was given every 3 weeks. At the time of relapse or progression, second-line chemotherapy was authorized before recourse to radiotherapy. Results: Objective response rate (partial response [PR] + complete response [CR]) to chemotherapy was 42%. Five-year progression-free survival (PFS) and overall survival rates were 34% and 89%, respectively. The 5-year radiotherapy-free survival rate was 61%. In the multivariate analysis of the 85 patients that entered onto the study, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P = .047) and absence of neurofibromatosis type 1 (P = .035). In the multivariate analysis of the 74 patients that remained on study after the first cycle of chemotherapy, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P = .0053) and no objective response to chemotherapy (P = .0029). Three-year PFS was 44% in infants ≤ 1 year versus 66% in children older than 1 year. Three-year PFS was 53% in the absence of an objective response to chemotherapy versus 68% after a PR or CR. Conclusion: A significant proportion of children with OPT can avoid radiotherapy after prolonged chemotherapy. Deferring irradiation with chemotherapy protocols did not compromise overall survival of the entire population or visual function.

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A Maintenance Therapy with Differentiating Agents and Low-Dose Chemotherapy Increases Remission Duration and Survival in High Risk AML and MDS Patients.

Blood ◽

10.1182/blood.v106.11.4614.4614 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4614-4614

Author(s):

Dario Ferrero ◽

Chiara Dellacasa ◽

Margherita Bonferroni ◽

Mariella Grasso ◽

Elisabetta Campa ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Maintenance Therapy ◽

Maintenance Treatment ◽

Low Dose ◽

Normal Karyotype ◽

Intensive Chemotherapy ◽

Actuarial Survival ◽

Maintenance Program ◽

Low Dose Chemotherapy

Abstract Acute myeloid leukemia (AML) patients above the age of 60 or with secondary AML generally have an unfavourable outcome. The same is true for high risk myelodysplastic syndrome (MDS) patients ineligible to bone marrow transplantation. Indeed, in spite of an improved CR rate after intensive chemotherapy (about 60–65%), median CR duration and survival remain short (9–12 months in most studies), due to early relapses. (Sekeres MA et al.: Curr Opin Oncol2002;14:24–30. Verbeek W et al.: Ann Hematol2001;80:499–509). On the basis of our previous clinical trials with differentiative agents + low dose chemotherapy in MDS/AML patients unsuitable to intensive treatments, (Ferrero D et al.: Leuk Res1996;20:867–876; Haematologica2004;89:619–620), we adopted the same strategy as a post-remission maintenance therapy to patients with AML or MDS at high risk of relapse and ineligible to allogeneic transplant. Thirty-six patients (27 AML and 9 high risk MDS) who had obtained a CR after different schemes of intensive chemotherapy were scheduled to receive the maintenance treatment with 13-cis-retinoic acid (20–40 mg/day) + 1,25-di-hydroxy-vitamin D3 (1 microgram /day) in association to intermittent, low dose chemotherapy: 6-thioguanine 40 mg/day x 21 days every 5 weeks, alternated every 2–3 months, in 24 patients, to a 14 day course of ARA-C 8 mg/m2 s.c. x 2/day + 6-mercaptopurine 50 mg/day. Patients’ median age was 64 years (range 27–76), with only 9 below the age of 60. Cytogenetic analysis was performed successfully in 27 cases, and an unfavourable karyotype was found in 10. All patients presented at least one poor prognosis determinant, including age >60 (27), previous AML relapse after autologous BMT (1), therapy-related disease (5), AML secondary to MDS (7), resistance to 1st induction therapy (4), hyperleukocytosis (8), RAEB-2 (8), abnormal karyotype (10). Twenty six had received 1 - 4 courses of consolidation treatment, including autologous stem cell transplantation in 2 MDS patients, before starting the maintenance program. Three patients underwent a very early relapse before maintenance start and 1 patient refused to prosecute the therapy after the first 2 months. The other 32 patients received the treatment as outpatients, with good tolerance and no major toxicity, until relapse, death or 4 years of continuous CR. After a median follow up for alive patients of 23 months (6–76), median disease-free (dfs) and overall survival, based on "intention to treat analysis" are 22 (1–74+) and 23 (5–76+) months, respectively, with a 28% 4 year actuarial survival. Inclusion of ARA-C in the maintenance treatment did not significantly prolong CR duration. The 17 patients with a normal karyotype enjoyed better median dfs (43 months) and overall survival (50,5 months) compared to the 10 patients with abnormal cytogenetics (12,5 and 15,5 months respectively); however, the differences are not significant, probably due to sample exiguity. In conclusion, our patients evidenced quite longer dfs and overall survival than expected from literature data on AML/MDS patients with similar features. However some late relapses (after 3–4 years) occurred. Therefore, our maintenance program seems worthy to be evaluated on larger casistics in randomised trials.

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Similar Outcomes among African-Americans (AA) and Whites after Autologous Hematopoietic-Cell Transplantation (Auto HCT) for Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v112.11.740.740 ◽

2008 ◽

Vol 112 (11) ◽

pp. 740-740 ◽

Cited By ~ 1

Author(s):

Parameswaran Hari ◽

Navneet S. Majhail ◽

Anna Hassebroek ◽

Mei-Jie Zhang ◽

Fareeha Siddiqui ◽

...

Keyword(s):

Overall Survival ◽

Renal Function ◽

African Americans ◽

Progression Free Survival ◽

Free Survival ◽

Post Transplant ◽

Transplant Outcomes ◽

Remission Status ◽

Response To Chemotherapy ◽

White Patients

Abstract MM is the most common hematological malignancy among AA adults and AA have twice the incidence and mortality from MM compared to Whites (SEER data, 2007). Based on CIBMTR registration rates of Auto HCT and incidence rates for MM, AA patients have been shown to have significantly lower likelihood of receiving Auto HCT (age adjusted odds ratio 0.58) compared to White patients with MM. The characteristics of AA patients who undergo Auto HCT for MM and their post transplant outcomes have not been compared to that of White MM patients. We compared characteristics and post-transplant outcomes of AA (N=303) and White (N=1892) patients receiving a first Auto HCT for MM and reporting to the CIBMTR between 1995 and 2005. Recipients of tandem Auto HCT were excluded. Compared to Whites, AA were significantly younger (29% aged <50 yr vs 21%, p=0.002), had better performance status at Auto HCT (69% with KPS score ≥90 vs 61%, p=0.005) and had higher incidence of hypertension (47% vs 25%, p<0.001), diabetes mellitus (17 % vs 9%, p<0.001) and morbid obesity (38% vs 31%, p=0.01). Durie-Salmon stage, immunoglobulin subtype, renal function, number of prior chemotherapy regimens, response to chemotherapy and remission status at transplant were similar in both groups. Transplant was more likely to be performed later (>12 months from diagnosis) in AA (37% vs 28% in Whites, p<0.001). The proportion of AA receiving Auto HCT increased from 7% in 1995 to 17% in 2004. No significant differences were found between AA and Whites in overall survival (52% vs 47%, at 5 years), progression-free survival (19% vs 21%, at 5 years), non-relapse mortality (3% vs 5%, at 1 year), or relapse (72% at 5 years in both groups) after Auto HCT. In multivariate analyses adjusting for patient, disease and transplant-related variables, race did not impact overall survival, progression-free survival, non-relapse mortality, or relapse (Table 1). We conclude that despite increased pre-transplant co-morbidities and transplantation later in the course of disease, post-transplant outcomes are comparable among AA and White patients who undergo Auto HCT for MM. The lower transplant rates in AA and the differences in pre-transplant patient characteristics need further investigation to explore racial differences in patient referral and selection for Auto HCT. Table 1: Multivariate analysis: African-Americans vs. Whites (reference group) Outcome Relative Risk 95% CI P-value Overall survival 0.94 0.78–1.13 0.50 Progression-free survival 0.94 0.81–1.09 0.42 Non-relapse mortality 1.16 0.75–1.80 0.51 Relapse 0.92 0.78–1.08 0.31 Adjusted for age, gender, KPS score at transplant, comorbidities (hypertension, diabetes, obesity, smoking), renal function, immunoglobulin subtype, Durie-Salmon stage, number of previous chemotherapy regimens, response to chemotherapy, remission status, time since diagnosis and year of transplant

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Final Analysis of Induction Treatment with Fludarabine, Cyclophosphamide Plus Rituximab (FCR) Followed by Fludarabine Plus Rituximab (FR) and Remission Maintenance Therapy with Rituximab In Previously Untreated B-Chronic Lymphocytic Leukemia (B-CLL): The Chairos AGMT CLL4/Roche ML18434 Study

Blood ◽

10.1182/blood.v116.21.1380.1380 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1380-1380

Author(s):

Alexander Egle ◽

Lukas Weiss ◽

Thomas Melchardt ◽

Eberhard Gunsilius ◽

Andreas L Petzer ◽

...

Keyword(s):

Maintenance Therapy ◽

Research Funding ◽

Maintenance Treatment ◽

Response Assessment ◽

Response To Therapy ◽

Clinical Staging ◽

Induction Treatment ◽

Rituximab Maintenance ◽

Best Response ◽

Remission Maintenance

Abstract Abstract 1380 Introduction: Intensification of treatment in CLL, specifically with FCR, has yielded impressive remission rates across almost all risk groups, with the exception of disease with del17p. However, despite initial remission patients relapsed with a median PFS time of 51.8 months in the CLL8 German randomized FCR trial, making remission maintenance an interesting concept. Study design: Three cycles of FCR, used initially to break potential resistance, were followed by 3 cycles of FR, with the intent to limit toxicities. Maintenance treatment was rituximab 375mg/m2 in 3 monthly intervals for 2 years. Here we report final results from this phase II study in previously untreated patients with CLL. Primary objective was the analysis of CR rates, according to NCI-WG criteria. An interim analysis of the induction phase of the study had been presented at ASH 2007. Results: We present 43 patients as intention-to-treat (ITT) population. The median age was 60 years (36 to 81), Rai stages III and IV were present in 21%, median β2-MG levels were 3.35 mg/L and 60% had at least one high risk factor out of mutation state, CD38 or FISH. Median follow up is currently 32 months. All ITT patients are evaluable for toxicity and 33 patients are evaluable for response after induction. 10 patients failed to reach the staging after the end of induction: 4 for septicemia/neutropenia, 1 for rituximab intolerance, 2 for hemolysis and 3 due to unrelated adverse events. The currently presented response assessment includes stringent use of CT scan results and is thus corrected from the 2007 interim results, obtained using clinical staging only. The response rates at the end of induction treatment were 27% CR, 36% CRi, 6% CRu, 21% PR and 9% SD. The previously reported high rate of CRi with incomplete marrow recovery argues that following FCR by FR did not improve tolerability. Nevertheless 81% of ITT patients were able to receive 6 cycles of therapy. Overall response and toxicity results are comparable with previously presented large datasets on FCR. A completely novel experience, however, is presented regarding the rituximab maintenance phase. Of the 43 ITT patients, 31 (72%) received at least one dose of maintenance treatment (the maintenance population). Regarding the maintenance population 74% finished all 8 cycles. Reasons to stop maintenance were: infections in 13% (all of them grade 1 and 2, although one patient died from herpetic encephalitis, 4 months after maintenance treatment had been stopped for a grade 2 infection), leucopenia 3%, progressive disease in 3 % and patient wish in 6%. Surprisingly, only a maximal 10% drop in serum IgG or IgM levels was observed during 2 years of maintenance. Regarding response assessment 5/31 (16%) patients receiving maintenance treatment improved their responses and 7/7 patients in CRi after induction resolved their cytopenias during maintenance treatment. Progression-free survival (PFS) in the ITT population was 78% after 36 months and was not significantly influenced by age >60, mutation state, β2-MG > 3,5 mg/L, creatinine clearance <60ml/min or permitted comorbidities. However, positive DAT and best response to therapy as well as an early drop in measured MRD levels predicted PFS. Two patients with del17p had expected inferior PFS, while none of the 5 patients with del11q has relapsed yet. Considering only the maintenance population, the PFS at 36 months was 77% and an overall best response of CR/CRu during maintenance led to a PFS of 91% after 36 months. Conclusion: Induction with an FCR like-induction protocol followed by rituximab maintenance proved feasible. However, 28% of the ITT population did not start maintenance treatment and 18% (ITT) could not finish the maintenance treatment, although no severe toxicities were responsible for the latter. One toxic death was observed, which is in the range reported for FCR without maintenance. Noteworthy, we did not find an influence of mutation state or β2-MG on PFS as has been previously reported, making it interesting to speculate that maintenance may be able to overcome such risk factors at least in mid-term, while keeping in mind the limited size of our sample. We currently run a multi-national randomized trial comparing rituximab maintenance with observation after R-containing induction in 1st and 2nd line that may be able to more definitely answer these questions (NCT01118234). Disclosures: Egle: Roche: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Rituximab maintenance therapy in CLL. Petzer:Roche: Honoraria. Fridrik:Roche: Honoraria, Speakers Bureau. Greil:Roche: Honoraria, Research Funding, Speakers Bureau.

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